tbuckley/cabot-search huggingface dataset:
Abstract LB206: Characterizing the PK/PD relationship of C/EBPβ antagonist peptide ST101 in a mouse orthotopic breast cancer model
Authors: Jim Rotolo, Mark Koester, Rick Ramirez, Erin Gallagher, Lila Ghamsari, Siok Leong, Emad Darvishi, Jerel Gonzales, Timothy Taylor, Richard Upton, Gene Merutka, Barry Kappel
Journal: Cancer Research (2022)

Abstract The transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) is aberrantly activated in many cancers, where it drives a genetic profile that promotes survival and proliferation of tumor cells and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ that prevents its dimerization by binding the leucine zipper domain, ultimately targeting C/EBPβ for proteosomal degradation. Here we describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of ST101 in a non-clinical orthotopic breast cancer model. An integrated population PK/PD model was developed to describe the exposure−response relationship for ST101 anti-tumor activity in female Balb/c mice bearing 4T1-luc triple-negative breast cancer orthotopic tumors. Exposure−response predictions were made based on estimated potency in mice and mean plasma concentrations observed at the doses investigated. Approximately 100% tumor growth inhibition (TGI) was observed at the highest doses administered in this study. The AUC values required to achieve IC50 and IC90 were 80,500 and 99,600 ng/ml*hr, respectively, corresponding to cumulative doses of 97 mg/kg and 120 mg/kg per week in mice. The integrated model provides a useful tool to characterize and predict the ST101 dose-response relationship, provide a quantitative rationale for dose selection in a phase 2 clinical trial and supports the continued development of ST101 as a potent peptide therapeutic for patients with solid tumors. Citation Format: Jim Rotolo, Mark Koester, Rick Ramirez, Erin Gallagher, Lila Ghamsari, Siok Leong, Emad Darvishi, Jerel Gonzales, Timothy Taylor, Richard Upton, Gene Merutka, Barry Kappel. Characterizing the PK/PD relationship of C/EBPβ antagonist peptide ST101 in a mouse orthotopic breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB206.
PB2320: AN INDICTION OF TREATING ADULT HEMOPHILIA IN A DEVELOPING COUNTRY: A RETROSPECTIVE ANALYSIS OF A SINGLE CENTER EXPERIENCE “PART I DESCRIPTIVE EPIDEMIOLOGY”
Authors: M. Elbogdady, S. Shamaa, M. Nasr, E. Azmy, M. Elzaafarany, T. Abo Zeid, M. Taalab, N. Eissa, S. Saber, M. Denwar, H. Elkerdawy, Y. Essam, M. Atef, B. Atef, A. Mohsen, E. Jamal, M. Saafan, A. Aly, A. Talaat, A. Elazab, A. Elshamy, S. Dheim, Y. Hamouda, R. Ibrahim, M. Awad, D. Ashraf, N. Elbayomy, A. Mokhtar, A. Sasy, E. Ebrahim
Journal: HemaSphere (2022)

Background: Hemophilias are the most frequent Inherited bleeding disorders. In Egypt which has a population of approximately(80 million) consanguineous marriage are frequent, there fore recessive coagulation disorders reach a higherprevalence than in many other countries. Aims: The aim of this study was to describe the epidemiological situation of adult hemophilia in Mansoura, Egypt as basedon retrospective analysis of our electronic clinical records at hematology unit Oncology center mansoura university (OCMU) between 2006 and 2021. Methods: Adult patients complaining of hemophilia were recruited from hematology unit at OCMU from 2006 to 2021.Demographic characteristics, clinical history, and laboratory and treatment data together with long term complications were collected. Results: The study included 117 recorded cases of Hemophilia (93 A & 24 B). Almost all the cases were previously diagnosedand were either on follow up with a pediatric unit and got their service transferred to our unit or came with ableeding emergency or for preoperative assessment. Male were 105 with 12 females with the females being 10 in A &only 2 in B. The mean age of first follow up at OCMU was 24.7 years with the minimum and the maximum being 17 & 54 years. The severity of hemophilia was distributed as follows 22% severe, 30 % moderate and the remaining 48%mild. HCV infection was found in 38 % of cases due to increased plasma transfusion being the main line of treatment. Summary/Conclusion: Dealing with adult hemophilia in a developing country is hard due to limited access to factor and poor patientcompliance and the transfusion related infections and complication are very hazardous & frequent with poor controlof bleeding episodes and joint affection leading to loss of patient’s adherence and increased adverse events
Continuing, reducing, switching, or stopping antipsychotics in individuals with schizophrenia-spectrum disorders who are clinically stable: a systematic review and network meta-analysis
Authors: Giovanni Ostuzzi, Giovanni Vita, Federico Bertolini, Federico Tedeschi, Beatrice De Luca, Chiara Gastaldon, Michela Nosé, Davide Papola, Marianna Purgato, Cinzia Del Giovane, Christoph U Correll, Corrado Barbui
Journal: The Lancet Psychiatry (2022)
P1703: ECONOMIC BURDEN OF TRANSFUSION-DEPENDENT BETA-THALASSEMIA IN THE UNITED STATES
Authors: C. Udeze, R. McKenna, Y. Yang, K. Evans, P. Smith, B. Andemariam
Journal: HemaSphere (2022)

Background: Transfusion-dependent beta-thalassemia (TDT) is a genetic blood disorder whose treatment is characterized by lifelong red blood cell transfusions (RBCTs) and iron chelation therapy (ICT). Aims: This study aims to describe the economic burden of patients with TDT in the United States (US). Methods: This retrospective cohort study used administrative claims from US MarketScan Commercial, Medicare, and Medicaid Multi-state databases to identify patients with ≥1 inpatient or ≥2 outpatient claims for beta-thalassemia or Hemoglobin E/beta-thalassemia between March 1, 2010 – March 1, 2019. Eligible patients with TDT were required to have ≥8 RBCTs in any 12-month period on or after the date of the earliest qualifying beta-thalassemia claim (first RBCT date = index date) and at least 12 months of post-index continuous enrollment with medical and pharmacy benefits. At least 3 days between service dates of RBCT claims were required to be considered discrete RBCTs. Patients were followed from index date to insurance disenrollment, death, or end of study period (March 1, 2020), whichever came first. Patients with hematopoietic stem cell transplant or sickle cell disease claims were excluded from this analysis. Baseline demographics, RBCT frequency, healthcare resource utilization, and costs were summarized per patient per year (PPPY). Results: A total of 4,504 patients with a diagnosis of beta-thalassemia were identified, of which 198 met criteria for TDT and other inclusion/exclusion criteria. Mean patient age at index date was 22.6 years and 56.6% were female; 81.8% of patients were in the Commercial database, 16.7% in Medicaid, and 1.5% in Medicare. Patients received a mean 12.52 RBCTs annually. Mean total annual healthcare costs were $137,987 PPPY. Mean annual costs of RBCTs were $27,887 and ICT were $70,402 PPPY. Summary/Conclusion: There is a significant economic burden with care of TDT patients in the US driven by chronic RBCTs and ICTs.
ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain
Authors: Gennady G. Yegutkin, Detlev Boison
Journal: Pharmacological Reviews (2022)

Adenosine is an evolutionary ancient metabolic regulator linking energy state to physiologic processes, including immunomodulation and cell proliferation. Tumors create an adenosine-rich immunosuppressive microenvironment through the increased release of ATP from dying and stressed cells and its ectoenzymatic conversion into adenosine. Therefore, the adenosine pathway becomes an important therapeutic target to improve the effectiveness of immune therapies. Prior research has focused largely on the two major ectonucleotidases, ectonucleoside triphosphate diphosphohydrolase 1/cluster of differentiation (CD)39 and ecto-5′-nucleotidase/CD73, which catalyze the breakdown of extracellular ATP into adenosine, and on the subsequent activation of different subtypes of adenosine receptors with mixed findings of antitumor and protumor effects. New findings, needed for more effective therapeutic approaches, require consideration of redundant pathways controlling intratumoral adenosine levels, including the alternative NAD-inactivating pathway through the CD38-ectonucleotide pyrophosphatase phosphodiesterase (ENPP)1-CD73 axis, the counteracting ATP-regenerating ectoenzymatic pathway, and cellular adenosine uptake and its phosphorylation by adenosine kinase. This review provides a holistic view of extracellular and intracellular adenosine metabolism as an integrated complex network and summarizes recent data on the underlying mechanisms through which adenosine and its precursors ATP and ADP control cancer immunosurveillance, tumor angiogenesis, lymphangiogenesis, cancer-associated thrombosis, blood flow, and tumor perfusion. Special attention is given to differences and commonalities in the purinome of different cancers, heterogeneity of the tumor microenvironment, subcellular compartmentalization of the adenosine system, and novel roles of purine-converting enzymes as targets for cancer therapy. <h3>Significance Statement</h3> The discovery of the role of adenosine as immune checkpoint regulator in cancer has led to the development of novel therapeutic strategies targeting extracellular adenosine metabolism and signaling in multiple clinical trials and preclinical models. Here we identify major gaps in knowledge that need to be filled to improve the therapeutic gain from agents targeting key components of the adenosine metabolic network and, on this basis, provide a holistic view of the cancer purinome as a complex and integrated network.
P1422: IN VIVO G-CSF TREATMENT ACTIVATES THE GR-SOCS1 AXIS TO SUPPRESS IFN-Γ SECRETION BY NATURAL KILLER CELLS
Authors: X. Cao, X. Zhao, T. Peng, Y. hou, R. Li, Z. Fan, M. Zhao, Y. chang, H. chen, C. li, X. Huang
Journal: HemaSphere (2022)

Background: Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in controlling tumors or microbial infections through the production of interferon gamma (IFN-γ). Granulocyte-colony stimulating factor (G-CSF) inhibits IFN-γ secretion by NK cells, but the mechanism underlying this effect remains unclear. Aims: To explore the mechanism of G-CSF on NK cells. Methods: Here, by comparing the multi-omics profiles of human NK cells before and after in vivo G-CSF treatment, we identified a pathway that was activated in response to G-CSF treatment, which suppressed IFN-γ secretion in NK cells. Specifically, our integrative genomic strategy revealed glucocorticoid receptor (GR) activation in NK cells that mediated the genomic response to G-CSF treatment. Results: Activated GRs can inhibit secretion of IFN-γ by promoting interactions between suppressor of cytokine signaling 1 (SOCS1) promoter and enhancer, as well as increase the expression of SOCS1. Experiments in mice confirmed that G-CSF in vivo treatment significantly down-regulated IFN-γ secretion and up- regulated GR and SOCS1 expression in NK cells. In addition, GR blockade (RU486) significantly reversed the effects of G-CSF, demonstrating that GR up-regulates SOCS1 and inhibits the production of IFN-γ by NK cells. Image:Summary/Conclusion: In this study, based on a HSC transplantation platform, we collected human bone marrow NK cells before and after G-CSF in vivo mobilization. By comparing the multi-omics profiles of NK cells before and after G-CSF treatment, we demonstrate that the glucocorticoid receptor (GR) mediates the genomic response to G-CSF treatment, and the GR- SOCS1 signal axis participates in reducing IFN-γ production by NK cells. Our work provides new potential avenues for therapeutic intervention for inflammatory diseases.
P1331: CENTRAL AND PERIPHERAL VENOUS ACCESSES SHOW NO DIFFERENCES IN EFFICIENCY OF CD34 + CELLS COLLECTION BY APHERESIS
Authors: J. C. De La Rosa García, B. Diaz Roldan, A. J. Palma Vallellano, A. R. Carranco Falcón, R. Zapata Bautista
Journal: HemaSphere (2022)

Background: Cytokine-mobilized peripheral blood stem cells (PBSCs) are the most common source in autologous and allogenic hematopoietic stem cell transplantation (HSCT) at present, displacing bone marrow harvest. Through apheresis we can obtain PBSCs, process that may be performed by different types of vascular accesses, either peripheral veins (PV) or central venous catheter (CVC). Nowadays there is no consensus on the superiority of one access over another in terms of quality of harvesting. Aims: The goal of this study is to compare both techniques in order to discover differences between them in the scope of efficiency. Methods: Our single-center study retrospectively revised and compared 155 apheresis process performed between July/2016 and October/2021. We defined collection efficiency, as the CD34+ cellularity obtained in relation to the expected (according to the processed volemia and the CD34+ pre-apheresis cells concentration in blood determined on a flow cytometer). Haematocrit, leukocytes, platelets and total proteins were compared in both groups to rule out differences, since several studies have shown that can influence in the collection efficiency. In our study CVC employed were Shaldon or Hickman. Results: Of 155 apheresis, 71 (45.81%) were performed through CVC, and 84 (54.19%) through PV. We also divided our sample according to sex and pathology (“sample” of Table 1). Differences in Haematocrit, leukocytes, platelets and total proteins are also showed at “pre-apheresis results” in Table 1. Finally, we focused in post-apheresis data. We analyzed: the efficiency of the procedure, the volume of collected product and the final count of CD34+ collected. We also analyzed the possible differences between both groups of patients, using the Student’s T technique, looking for statistically significant differences (p) between them (“post-apheresis results” of Table 1). Image:Summary/Conclusion: The results of our study reveal a similar efficiency regardless of the type of access used for apheresis. Therefore, taking into account the possible complications of central catheter venous access, as a higher rate of infection, thrombosis, pneumothorax, bleeding or the recirculation rate risk, it should be used only in patients with poor peripheral accesses.
PB1889: A CASE OF REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INDUCED IMMUNE THROMBOCYTOPENIC PURPURA SUCCESSFULLY TREATED WITH VENETOCLAX
Authors: B. Yavuz, A. F. Karatas, E. Erdogan Yucel, O. Seker, S. Guven, M. Kakci, G. H. Ozsan, I. Alacacioglu, F. Demirkan
Journal: HemaSphere (2022)

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Approximately 2% of patients with CLL develop immune thrombocytopenic purpura (ITP) during the course of the disease. When resistant to steroids, this constitutes as indication for treatment of the CLL. Here we report a patient with refractory ITP secondary to CLL successfully treated with venetoclax. Aims: To present an interesting case with CLL related refractory ITP treated successfully with novel agent venetoclax. Methods: Patient data was taken from the patient herself and hospital records. Informed consent to publish the case is obtained from patient. Permission for off-label venetoclax and eltrombopag was obtained from Ministry of Health of Turkey. Results: 46-year-old female patient presented with lumps on her neck that were present for the last 9 months in November 2020. She has a history of frequent pneumonia and otitis but no constitutional symptoms. Her physical examination reveals multiple 2cm lymphadenopathies on her neck and no organomegaly or other pathological features. Blood work shows mild lymphocytosis (6800/mm3) with no serious cytopenias. Peripheral blood smear, flow cytometry and bone marrow biopsy were all compatible with CLL. She was classified as Binet A CLL and was followed up with no treatment after appropriate vaccinations against capsulated pathogens. In July and August 2021 she received two doses of mRNA vaccination against COVID-19. On 1st November 2021 she experienced excessive menstrual bleeding and blood work showed platelet count of 23000/mm3, she was started on steroids (1 mg/kg/day) and after 4 days platelet count has risen to 55000/mm3, she discontinued steroids on her own against medical advice. On 13th of November she presented with extensive petechiae and purpura and was again started on steroids and was given the courses of intravenous immunoglobulins (IVIG) without any sustained response. She was refractory to platelet transfusions too. She was transferred to our clinic. She was found to have del11q and del13q. She refused bone marrow examination. She was treated with rituximab, steroids, vincristine, IVIG and eltrombopag for ITP without success (Fig. 1). She had a minimal response to IVIG only. She received two courses of bendamustine (90 mg/kg for two days) also without success. Three courses of plasmapheresis yielded no response either. After mild success with immunadsorbtion apharesis she was started on venetoclax plus rituximab with ramp-up. Sustained response was achieved within the first week of venetoclax therapy. Image:Summary/Conclusion: Gordon et al. reported 2 CLL cases one with ITP and other with Evans syndrome successfully treated with venetoclax. We think, this treatment should be considered in patients with refractory immune cytopenias secondary to CLL and assessed with prospective clinical trials.
P1310: A ROBUST APPROACH FOR THE GENERATION OF FUNCTIONAL HEMATOPOIETIC PROGENITOR CELL LINES TO MODEL LEUKEMIC TRANSFORMATION
Authors: E. Doma, I. Mayer, A. Hoelbl-Kovacic, R. Grausenburger, K. Kollmann, V. Sexl
Journal: HemaSphere (2022)

Background: Preclinical research aims at developing robust methods to maintain, expand and manipulate haematopoietic stem/progenitor cells (HSPC) ex vivo, as these cells are infrequent and their immortalization is hardly achieved. The transcription factor, LIM homeobox protein 2 (LHX2), has a critical role in maintaining self-renewal and has been reported to facilitate ex vivo expansion of immature HSPCs. Aims: We aimed to establish a robust and low-cost murine HSPC in vitro model system that allows maintenance and expansion of functional LSK (lin-, Sca-1+, c-Kit+) cells, and guarantees long-term multipotency. Methods: We generated HPCLSK cell lines from high-purity sorted murine LSK cells by Lhx2 overexpression. SCF/IL-6 dependent HPCLSK cells are kept on agarose-coated plates to prevent adherence-induced myeloid differentiation. HPCLSK cells can be genetically modified e.g. by retroviral transduction, which serves as a source to generate LSCs harboring hematopoietic stem cell oncogenes including BCR/ABLp210+, MLL-AF9 or FLT3-ITD/NRASG12D. Immunophenotyping, transcriptome analysis and functionality tests of HPCLSK and LSC lines were carried out. Results: HPCLSK cells preserve LSK markers despite continuous proliferation. HPCLSK cells efficiently home to the BM, blood, spleen, and thymus and are able to differentiate into myeloid and lymphoid lineages in vitro and in vivo. Numbers of HPCLSK–derived myeloid and lymphoid progenitors in the BM and differentiated blood cells are comparable to BM-injected mice. Transcriptome analysis of HPCLSK lines showed a ST-HSC/MPP1 signature, which corresponds to the earliest proliferating HSPCs. Injection of transformed HPCLSK-LSC (BCR/ABLp210, MLL-AF9, FLT3-ITD/NRASG12D) lines in immunocompromised mice induced myeloid leukemia. All diseased animals displayed elevated WBC counts, blast-like cells in the blood and suffered from splenomegaly. To test the applicability of the model system for drug sensitivity tests we employed Imatinib mesylate (IM). As in patients, HPCLSK-BCR/ABLp210 cells show partial IM resistance and leads to the enrichment of undifferentiated LSK cells. Summary/Conclusion: We created a robust method of culturing functional HSPCs, which are immortalized and can be expanded indefinitely. HPCLSK lines can be rapidly generated from transgenic mouse models and are a useful system for functional assays that require high cell numbers. By oncogenic transformation we created leukemia triggering LSCs. These findings support the relevance of HPCLSK cell system that represents a unique tool to compare LSCs to non-transformed HPCLSK cells in vitro and in vivo, which can be adapted for high-scale preclinical compound screening.
Modulating albumin-mediated transport of peptide-drug conjugates for antigen-specific Treg induction
Authors: Chun Yin Jerry Lau, Naomi Benne, Bo Lou, Olga Zharkova, Hui Jun Ting, Daniëlle ter Braake, Nicky van Kronenburg, Marcel H. Fens, Femke Broere, Wim E. Hennink, Jiong-Wei Wang, Enrico Mastrobattista
Journal: Journal of Controlled Release (2022)

The therapeutic potential of antigen-specific regulatory T cells (Treg) has been extensively explored, leading to the development of several tolerogenic vaccines. Dexamethasone-antigen conjugates represent a prominent class of tolerogenic vaccines that enable coordinated delivery of antigen and dexamethasone to target immune cells. The importance of nonspecific albumin association towards the biodistribution of antigen-adjuvant conjugates has gained increasing attention, by which hydrophobic and electrostatic interactions govern the association capacity. Using an ensemble of computational and experimental techniques, we evaluate the impact of charged residues adjacent to the drug conjugation site in dexamethasone-antigen conjugates (Dex-K/E4-OVA323, K: lysine, E: glutamate) towards their albumin association capacity and induction of antigen-specific Treg. We find that Dex-K4-OVA323 possesses a higher albumin association capacity than Dex-E4-OVA323, leading to enhanced liver distribution and antigen-presenting cell uptake. Furthermore, using an OVA323-specific adoptive-transfer mouse model, we show that Dex-K4-OVA323 selectively upregulated OVA323-specific Treg cells, whereas Dex-E4-OVA323 exerted no significant effect on Treg cells. Our findings serve as a guide to optimize the functionality of dexamethasone-antigen conjugate amid switching vaccine epitope sequences. Moreover, our study demonstrates that moderating the residues adjacent to the conjugation sites can serve as an engineering approach for future peptide-drug conjugate development.